Melatonin plays a critical role in regulating photoperiodic signals and has recently been shown to decrease immunosenescence with age.In this study,we examined whether melatonin activates T lymphocytes as major adaptive immune cells in in vitro and in vivo models.Splenocytes,CD4~+,and nave CD4 T lymphocytes were isolated from the spleen of BALB/c mice and the cell population patterns and mRNA profiles associated with T cell activation(CD28 and p21) and the melatonin receptor(MT1A and MT1B) were assessed.The T cell activationrelated proteins Ki67 and Bcl2 were also evaluated to confirm the relationship between gene and protein levels.Our data clearly revealed that CD28,p21,MT1 A,and MT1 B mRNA were highly expressed in the presence of melatonin.Co-culture of CD4~+ T lymphocyte and peritoneal macrophage 7 days after melatonin administration to young and aged mice significantly increased APRIL mRNA,suggesting induction or maintenance of T lymphocyte responses.We also found that the intracellular amount of Ki67 and Bcl2 proteins were significantly upregulated in aged CD4~+ T lymphocytes,suggesting enhancing T cell proliferation and ling-term maintenance of memory T cells.Taken together,we conclude that melatonin supplementation may enhance immunity in aged individuals by upregulating immunosenescence indices in association with T lymphocytes and may be an attractive pharmacological candidate for aged and immunocompromised individuals. Melatonin plays a critical role in regulated photoperiodic signals and has recently been shown to decrease immunosenescence with age. In this study, we examined whether melatonin activates T lymphocytes as major adaptive immune cells in vitro and in vivo models .plenocytes, CD4 ~ +, and nave CD4 T lymphocytes were isolated from the spleen of BALB / c mice and the cell population patterns and mRNA profiles associated with T cell activation (CD28 and p21) and the melatonin receptor (MT1A and MT1B) were. The T cell activationrelated proteins Ki67 and Bcl2 were also evaluated to confirm the relationship between gene and protein levels. Our data indicates that CD28, p21, MT1 A, and MT1 B mRNA were highly expressed in the presence of melatonin. Co-culture of CD4 ~ + T lymphocyte and peritoneal macrophage 7 days after melatonin administration to young and aged mice significantly increased APRIL mRNA, suggesting induction or maintenance of T lymphocyte responses. We also found that the intr acellular amount of Ki67 and Bcl2 proteins were significantly upregulated in aged CD4 ~ + T lymphocytes, suggesting enhancing T cell proliferation and ling-term maintenance of memory T cells. Taken together, we conclude that melatonin supplementation may enhance immunity in aged individuals by upregulating immunosenescence indices in association with T lymphocytes and may be an attractive pharmacological candidate for aged and immunocompromised individuals.